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Saturday, May 5, 2018

May 2018

Prenatal Primary Prevention of Mental Illness by Micronutrient Supplements in Pregnancy

The American Journal of Psychiatry

People who eat vegetables, fruit and whole grains may have lower rates of depression over time, according to a preliminary study released today that will be presented at the American Academy of Neurology’s 70th Annual Meeting in Los Angeles, April 21 to 27, 2018.

The study found that people whose diets adhered more closely to the Dietary Approaches to Stop Hypertension (DASH) diet were less likely to develop depression than people who did not closely follow the diet. In addition to fruit and vegetables, the DASH diet recommends fat-free or low-fat dairy products and limits foods that are high in saturated fats and sugar. Studies have shown health benefits such as lowering high blood pressure and bad cholesterol (LDL), along with lowering body weight.

“Depression is common in older adults and more frequent in people with memory problems, vascular risk factors such as high blood pressure or high cholesterol, or people who have had a stroke,” said study author Laurel Cherian, MD, of Rush University Medical Center in Chicago and a member of the American Academy of Neurology. “Making a lifestyle change such as changing your diet is often preferred over taking medications, so we wanted to see if diet could be an effective way to reduce the risk of depression.”

For the study, 964 participants with an average age of 81 were evaluated yearly for an average of six-and-a-half years. They were monitored for symptoms of depression such as being bothered by things that usually didn’t affect them and feeling hopeless about the future. They also filled out questionnaires about how often they ate various foods, and the researchers looked at how closely the participants’ diets followed diets such as the DASH diet, Mediterranean diet and the traditional Western diet. 

Antidepressants and suicidal behaviour in late life: a prospective population-based study of use patterns in new users aged 75 and above

European Journal of Clinical Pharmacology


To investigate associations between antidepressant use patterns and risk of fatal and non-fatal suicidal behaviours in older adults who initiated antidepressant therapy.

A national population-based cohort study conducted among Swedish residents aged ≥ 75 years who initiated antidepressant treatment. Patients who filled antidepressant prescriptions between January 1, 2007 and December 31, 2013 (N = 185,225) were followed until December 31, 2014. Sub-hazard ratios of suicides and suicide attempts associated with use patterns of antidepressants, adjusting for potential confounders such as serious depression were calculated using the Fine and Gray regression models.

During follow-up, 295 suicides and 654 suicide attempts occurred. Adjusted sub-hazard ratios (aSHRs) were increased for both outcomes in those who switched to another antidepressant (aSHR for suicide 2.42, 95% confidence interval 1.65 to 3.55, and for attempt 1.76, 1.32 to 2.34). Elevated suicide risks were also observed in those who concomitantly filled anxiolytics (1.54, 1.20 to 1.96) and hypnotics (2.20, 1.69 to 2.85). Similar patterns were observed for the outcome suicide attempt. Decreased risk of attempt was observed among those with concomitant use of anti-dementia drugs (0.40, 0.27 to 0.59).

Switching antidepressants, as well as concomitant use of anxiolytics or hypnotics, may constitute markers of increased risk of suicidal behaviours in those who initiate antidepressant treatment in very late life. Future research should consider indication biases and the clinical characteristics of patients initiating antidepressant therapy.  

Lamotrigine: Drug Safety Communication - Serious Immune System Reaction

ISSUE: The FDA is warning that the medicine Lamictal (lamotrigine) for seizures and bipolar disorder can cause a rare but very serious reaction that excessively activates the body’s infection-fighting immune system. This can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly. As a result, we are requiring a new warning about this risk be added to the prescribing information in the lamotrigine drug labels.

BACKGROUND: The immune system reaction, called hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled response by the immune system. HLH typically presents as a persistent fever, usually greater than 101°F, and it can lead to severe problems with blood cells and organs throughout the body such as the liver, kidneys, and lungs.

Lamotrigine is used alone or with other medicines to treat seizures in patients two years and older. It may also be used as maintenance treatment in patients with bipolar disorder to help delay the occurrence of mood episodes such as depression, mania, or hypomania. Stopping lamotrigine without first talking to a prescriber can lead to uncontrolled seizures, or new or worsening mental health problems. Lamotrigine has been approved and on the market for 24 years, and is available under the brand name Lamictal and as generics.

RECOMMENDATION: Healthcare professionals should be aware that prompt recognition and early treatment is important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific. HLH may also be confused with other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Evaluate patients who develop fever or rash promptly, and discontinue lamotrigine if HLH or another serious immune-related adverse reaction is suspected and an alternative etiology for the signs and symptoms cannot be established. Advise patients to seek immediate medical attention if they experience symptoms of HLH during lamotrigine treatment. A diagnosis of HLH can be established if a patient has at least five of the following eight signs or symptoms:

- fever and rash

- enlarged spleen

- cytopenias

- elevated levels of triglycerides or low blood levels of fibrinogen

- high levels of blood ferritin

- hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy

- decreased or absent Natural Killer (NK) Cell activity

- elevated blood levels of CD25 showing prolonged immune cell activation

Patients or their caregivers should contact their health care professionals right away if they experience any symptom of HLH while taking lamotrigine. HLH can occur within days to weeks after starting treatment. A physical examination and specific laboratory blood tests and other evaluations are used to diagnose HLH. Signs and symptoms of HLH include but are not limited to:

- fever

- enlarged liver; symptoms may include pain, tenderness, or unusual swelling over the liver area in the upper right belly

- swollen lymph nodes

- skin rashes

- yellow skin or eyes

- unusual bleeding

- nervous system problems, including seizures, trouble walking, difficulty seeing, or other visual disturbances

Read the patient Medication Guide, which explains the benefits and risks of lamotrigine, every time you get a new prescription because the information may change. Do not stop taking lamotrigine without talking to your health care professional first as doing so can cause serious problems.

Altered Brain Developmental Trajectories in Adolescents After Initiating Drinking

The American Journal of Psychiatry 


The authors sought evidence for altered adolescent brain growth trajectory associated with moderate and heavy alcohol use in a large national, multisite, prospective study of adolescents before and after initiation of appreciable alcohol use.

This study examined 483 adolescents (ages 12–21) before initiation of drinking and 1 and 2 years later. At the 2-year assessment, 356 participants continued to meet the study’s no/low alcohol consumption entry criteria, 65 had initiated moderate drinking, and 62 had initiated heavy drinking. MRI was used to quantify regional cortical and white matter volumes. Percent change per year (slopes) in adolescents who continued to meet no/low criteria served as developmental control trajectories against which to compare those who initiated moderate or heavy drinking.

In no/low drinkers, gray matter volume declined throughout adolescence and slowed in many regions in later adolescence. Complementing gray matter declines, white matter regions grew at faster rates at younger ages and slowed toward young adulthood. Youths who initiated heavy drinking exhibited an accelerated frontal cortical gray matter trajectory, divergent from the norm. Although significant effects on trajectories were not observed in moderate drinkers, their intermediate position between no/low and heavy drinkers suggests a dose effect. Neither marijuana co-use nor baseline volumes contributed significantly to the alcohol effect.

Initiation of drinking during adolescence, with or without marijuana co-use, disordered normal brain growth trajectories. Factors possibly contributing to abnormal cortical volume trajectories include peak consumption in the past year and family history of alcoholism.

Alzheimer’s Disease Can Be Spared by Nonsteroidal Anti-Inflammatory Drugs

Journal of Alzheimer’s Disease


Alzheimer’s disease (AD) is characterized by deposits of amyloid- protein (A) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of A42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of A42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40–85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD.

Neural Markers of Resilience in Adolescent Females at Familial Risk for Major Depressive Disorder

JAMA Psychiatry

Mental illness affects one in six U.S. adults, but scientists' sense of the underlying biology of most psychiatric disorders remains nebulous. That's frustrating for physicians treating the diseases, who must also make diagnoses based on symptoms that may only appear sporadically. No laboratory blood test or brain scan can yet distinguish whether someone has depression or bipolar disorder, for example.

Now, however, a large-scale analysis of postmortem brains is revealing distinctive molecular traces in people with mental illness. This week, an international team of researchers reports that five major psychiatric disorders have patterns of gene activity that often overlap but also vary in disease-specific—and sometimes counterintuitive—ways. The findings, they say, might someday lead to diagnostic tests and novel therapies, and one has already inspired a clinical trial of a new way to treat overactive brain cells in autism.

Outsiders say the data mark a milestone in psychiatry. "This [work] is changing fundamental views about the nature of psychiatric illness," says Kenneth Kendler, a psychiatric geneticist at Virginia Commonwealth University in Richmond.

Human Hippocampal Neurogenesis Persists throughout Aging

Cell Stem Cell


Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

The effect of curcumin (turmeric) on Alzheimer's disease: An overview

Annals of Indian Academy of Neurology


This paper discusses the effects of curcumin on patients with Alzheimer's disease (AD). Curcumin (Turmeric), an ancient Indian herb used in curry powder, has been extensively studied in modern medicine and Indian systems of medicine for the treatment of various medical conditions, including cystic fibrosis, haemorrhoids, gastric ulcer, colon cancer, breast cancer, atherosclerosis, liver diseases and arthritis. It has been used in various types of treatments for dementia and traumatic brain injury. Curcumin also has a potential role in the prevention and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD. A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer's disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. This paper reviews the various mechanisms of actions of curcumin in AD and pathology.

The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis

Child & Adolescent Psychiatry


To determine the trajectory and magnitude of antidepressant response as well as the effect of antidepressant class and dose on symptomatic improvement in pediatric anxiety disorders.

Weekly symptom severity data were extracted from randomized, parallel group, placebo-controlled trials of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin−norepinephrine reuptake inhibitors (SNRIs) in pediatric anxiety disorders. Treatment response was modeled for the standardized change in continuous measures of anxiety using Bayesian updating. Posterior distributions for each study served as informative conjugate prior to distributions update subsequent study posteriors. Change in symptom severity was evaluated as a function of time, class and, for SSRIs, standardized dose.

Data from 9 trials (SSRIs: n = 5; SNRIs, n = 4) evaluating 7 medications in 1,673 youth were included. In the logarithmic model of treatment response, statistically, but not clinically, significant treatment effects emerged within 2 weeks of beginning treatment (standardized medication−placebo difference = −0.054, credible interval [CI] = −0.076 to −0.032, p = .005, approximate Cohen’s d ≤ 0.2) and by week 6, clinically significant differences emerged (standardized medication−placebo difference = −0.120, CI = −0.142 to −0.097, p = .001, approximate Cohen’s d = 0.44). Compared to SNRIs, SSRIs resulted in significantly greater improvement by the second week of treatment (p = .0268), and this advantage remained statistically significant through week 12 (all p values <.03). Improvement occurred earlier with high-dose SSRI treatment (week 2, p = .002) compared to low-dose treatment (week 10, p = .025), but SSRI dose did not have an impact on overall response trajectory (p > .18 for weeks 1−12).

In pediatric patients with generalized, separation, and/or social anxiety disorders, antidepressant-related improvement occurred early in the course of treatment, and SSRIs were associated with more rapid and greater improvement compared to SNRIs.

Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders

Journal of Psychopharmacology


In this maintenance treatment study, we sought to evaluate the effect on anxiety ratings, safety and tolerability of 3 months of weekly ketamine in 20 patients with treatment-refractory DSM IV generalised anxiety disorder (GAD) and/or social anxiety disorder (SAD), and subsequent assessment of remission post-treatment.

This was an uncontrolled open-label study in 20 patients who had been responders in an ascending dose ketamine study. The study was undertaken in a university clinic. Patients received one or two weekly ketamine doses of 1 mg/kg injected subcutaneously for 3 months. Data were collected from December 2015–June 2017.

There were 10 women (50%) and 10 men (50%); 15 patients (75%) met criteria for GAD and 18 (90%) for SAD. One hour after dosing, Fear Questionnaire ratings decreased by ~50%, as did Hamilton Anxiety ratings. Clinician Administered Dissociative States Scale mean scores declined over time, from 20 points at week 1 to 8.8 points at week 14. Compared with pre-dose values, mean systolic and diastolic blood pressure increased by ~10 mm Hg at 30 min. The most common adverse events were nausea, dizziness and blurred vision. Of the 20 patients, 18 reported improved social functioning and/or work functioning during maintenance treatment.

Weekly ketamine dosing was safe and well tolerated, and post-dose dissociative symptoms tended to reduce after repeated dosing. Patients reported marked improvements in functionality and in their personal lives. Maintenance ketamine may be a therapeutic alternative for patients with treatment refractory GAD/SAD.

Online Journals:

Biological Psychiatry - Volume 83, Issue 10, May 2018

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